title: Epidermal growth factor receptor and claudin-2 participate in A549 permeability and remodeling: implications for non-small cell lung cancer tumor colonization.
abstract: Tumor colonization involves changes in cell permeability and remodeling. Paracellular permeability is regulated by claudins, integrated tight junction (TJ) proteins, located on the apicolateral portion of epithelial cells. Epidermal growth factor (EGF) was reported to modify cellular claudin levels and induce remodeling. To investigate a role for EGF receptor (EGFR) activation in tumor colonization we studied the effect of EGF and claudin-2 overexpression on permeability and cell reorganization in the human A549 non-small cell lung cancer (NSCLC) cell line. Our data demonstrated that A549 cells possess functional TJs and that EGF treatment increased levels of claudin-2 expression by 46%. Furthermore, EGFR signaling reduced monolayer permeability to choline and triggered cellular remodeling. The mitogen-activated protein kinase inhibitor PD98059 blocked the effect on A549 permeability and remodeling. EGF stimulation also exacerbated a fourfold increase in cell colonization elicited by claudin-2 upregulation. Our findings are consistent with the hypothesis that EGFR signaling plays an important role in A549 cell physiology and acts synergistically with claudin-2 to accelerate tumor colonization. Understanding the influence of EGF on A549 cell permeability and reorganization will help shed light on NSCLC tumor colonization and contribute to the development of novel anti-cancer treatments.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yakov
authors.initials: Y
authors.lastname: Peter
authors.forename: Alejandro
authors.initials: A
authors.lastname: Comellas
authors.forename: Elena
authors.initials: E
authors.lastname: Levantini
authors.forename: Edward P
authors.initials: EP
authors.lastname: Ingenito
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D057167:Claudins; D017931:DNA Primers; D066246:ErbB Receptors / Q000378:metabolism / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: C491875:CLDN2 protein, human; D057167:Claudins; D017931:DNA Primers; D005419:Flavonoids; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one